The impact of warfarin on the rate of progression of aortic stiffness in hemodialysis patients: a longitudinal study

Poulin, Aurélie; Utescu, Mihai Silviu; Serres, Sacha A. De; Marquis, Karine; Douville, Pierre; Desmeules, Simon; Lariviere, Richard W.; Lebel, Marcel; Agharazii, Mohsen

doi:10.1093/ndt/gfu224

Cited by 38 publications

(29 citation statements)

References 38 publications

(46 reference statements)

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“…The results from this large population sample are supported by data from the literature: an observational study reported that warfarin administration is associated with a rapid progression of aortic stiffness in patients undergoing hemodialysis 11. Arterial stiffness is influenced by the calcification of the elastic components of the artery wall, leading to hypertension.…”

Section: Discussionsupporting

confidence: 72%

Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population‐Based Gutenberg Health Study

Eggebrecht

Prochaska

Schulz

et al. 2018

JAHA

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BackgroundPreclinical data have indicated a link between use of vitamin K antagonists (VKA) and detrimental effects on vascular structure and function. The objective of the present study was to determine the relationship between VKA intake and different phenotypes of subclinical cardiovascular disease in the population.Methods and ResultsClinical and laboratory data, as well as medical–technical examinations were assessed from 15 010 individuals aged 35 to 74 years during a highly standardized 5‐hour visit at the study center of the population‐based Gutenberg Health Study. In total, the study sample comprised 287 VKA users and 14 564 VKA nonusers. Multivariable analysis revealed an independent association between VKA intake and stiffness index (β=+2.54 m/s; [0.41/4.66]; P=0.019), ankle‐brachial index (β=−0.03; [−0.04/−0.01]; P<0.0001), intima‐media thickness (β=+0.03 mm [0.01/0.05]; P=0.0098), left ventricular ejection fraction (β=−4.02% [−4.70/−3.33]; P<0.0001), E/E′ (β=+0.04 [0.01/0.08]; P=0.014) left ventricular mass (β=+5.34 g/m2.7 [4.26/6.44]; P<0.0001), and humoral markers of cardiac function and inflammation (midregional pro‐atrial natriuretic peptide: β=+0.58 pmol/L [0.50/0.65]; P<0.0001; midregional pro‐adrenomedullin: β=+0.18 nmol/L [0.14/0.22]; P<0.0001; N‐terminal pro B‐type natriuretic peptide: β=+1.90 pg/mL [1.63/2.17]; P<0.0001; fibrinogen: β=+143 mg/dL [132/153]; P<0.0001; C‐reactive protein: β=+0.31 mg/L [0.20/0.43]; P<0.0001). Sensitivity analysis in the subsample of participants with atrial fibrillation stratified by intake of VKA demonstrated consistent and robust results. Genetic variants in CYP2C9,CYP4F2, and VKORC1 were modulating effects of VKA on subclinical markers of cardiovascular disease.ConclusionsThese data demonstrate negative effects of VKA on vascular and cardiac phenotypes of subclinical cardiovascular disease, indicating a possible influence on long‐term disease development. These findings may be clinically relevant for the provision of individually tailored antithrombotic therapy.

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Section: Discussionsupporting

confidence: 72%

Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population‐Based Gutenberg Health Study

Eggebrecht

Prochaska

Schulz

et al. 2018

JAHA

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“…In a case-control study with a mean follow up of 1.2 years, 18 hemodialysis patients on warfarin had a greater increase in PWV than controls not on warfarin. 30 Controls were age-matched (±2 years) and also on hemodialysis. All participants were free of previous cardiovascular disease.…”

Section: Discussionmentioning

confidence: 99%

Inactive Matrix Gla-Protein Is Associated With Arterial Stiffness in an Adult Population–Based Study

et al. 2015

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Increased pulse wave velocity (PWV) is the gold standard in assessing stiffening of the aorta.1 As shown by 3 population studies, all including over thousand participants, PWV refines risk stratification above and beyond traditional cardiovascular risk factors. In multivariable-adjusted analyses, per one standard deviation (SD) increment in PWV, cardiovascular mortality increased by 20% and 60% in a Danish and Taiwanese population samples, respectively.2,3 The Framingham heart study found that one standard deviation increment of PWV was associated with a 48% increase in cardiovascular disease risk. 4 Matrix Gla-protein (MGP) is acting as a strong inhibitor of soft tissue calcification. 5,6 MGP knockout mice develop massive vascular calcification in their first weeks of life and die within 2 months of vessels rupture.7 MGP is expressed primarily by chondrocytes and vascular smooth muscle cells. 8,9 To acquire its full calcification inhibitory activity, MGP needs to undergo 2 post-translational modifications: glutamate carboxylation and serine phosphorylation. Both modifications are not exerted completely, so theoretically, 4 different MGP conformations can be found: unmodified and Abstract-Increased pulse wave velocity (PWV) is a marker of aortic stiffness and an independent predictor of mortality.Matrix Gla-protein (MGP) is a vascular calcification inhibitor that needs vitamin K to be activated. Inactive MGP, known as desphospho-uncarboxylated MGP (dp-ucMGP), can be measured in plasma and has been associated with various cardiovascular markers, cardiovascular outcomes, and mortality. In this study, we hypothesized that high levels of dp-ucMGP are associated with increased PWV. We recruited participants via a multicenter family-based crosssectional study in Switzerland. Dp-ucMGP was quantified in plasma by sandwich ELISA. Aortic PWV was determined by applanation tonometry using carotid and femoral pulse waveforms. Multiple regression analysis was performed to estimate associations between PWV and dp-ucMGP adjusting for age, renal function, and other cardiovascular risk factors. We included 1001 participants in our analyses (475 men and 526 women). Mean values were 7.87±2.10 m/s for PWV and 0.43±0.20 nmol/L for dp-ucMGP. PWV was positively associated with dp-ucMGP both before and after adjustment for sex, age, body mass index, height, systolic and diastolic blood pressure (BP), heart rate, renal function, low-and high-density lipoprotein, glucose, smoking status, diabetes mellitus, BP and cholesterol lowering drugs, and history of cardiovascular disease (P≤0.01). In conclusion, high levels of dp-ucMGP are independently and positively associated with arterial stiffness after adjustment for common cardiovascular risk factors, renal function, and age. inactive as desphospho-uncarboxylated MGP (dp-ucMGP), only phosphorylated, only carboxylated, and finally fully modified and active as phosphorylated and carboxylated MGP. 10,11 Carboxylation of MGP is a vitamin K-dependent process: vitamin K hydroquinone, a vitamin K m...

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“…Hence, previous studies on HD patients might have overlooked the early benefit of oral anticoagulants because they excluded patients dying within 30-90 days since the diagnosis of AF [15,16,20] . Additionally, patients treated with VKA for prolonged time (greater than 1 year) have a higher risk of vascular calcifications [44,47] and increased arterial stiffness [48] , two major risk factors for cardiovascular mortality [49] , independent of other well-known risk factors including serum levels of bone markers. Such effects are similar to those observed in patients with vitamin K deficiency [50] and might be particularly strong in HD patients for whom the activity of Matrix γ-carboxyglutamate proteins, a group of vitamin K-dependent proteins inhibiting vascular mineral deposition, is severely hampered [29,47,48] .…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, patients treated with VKA for prolonged time (greater than 1 year) have a higher risk of vascular calcifications [44,47] and increased arterial stiffness [48] , two major risk factors for cardiovascular mortality [49] , independent of other well-known risk factors including serum levels of bone markers. Such effects are similar to those observed in patients with vitamin K deficiency [50] and might be particularly strong in HD patients for whom the activity of Matrix γ-carboxyglutamate proteins, a group of vitamin K-dependent proteins inhibiting vascular mineral deposition, is severely hampered [29,47,48] . Our design cannot completely rule out the alternative hypothesis that residual bias by indication affected our risk estimates.…”

Section: Discussionmentioning

confidence: 99%

Patients' Characteristics Affect the Survival Benefit of Warfarin Treatment for Hemodialysis Patients with Atrial Fibrillation. A Historical Cohort Study

Brancaccio

Neri²,

Bellocchio³

et al. 2016

Am J Nephrol

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Background: Stroke prevention in dialysis-dependent patients with atrial fibrillation (AF) is an unresolved clinical dilemma. Indeed, no randomized controlled trial evaluating the efficacy and safety of oral anticoagulants in this population, has been conducted so far. Observational research on the use of warfarin in patients on dialysis has shown conflicting results. This uncertainty is mirrored by the wide variations in warfarin prescription patterns across centers. We sought to evaluate the association between the use of vitamin K antagonists (VKAs) and mortality among hemodialysis patient with AF and to assess potential factors affecting the risk-benefit profile of warfarin in this population. Methods: A total of 91,987 patients registered in the European Clinical Dialysis Database® system from January 2004 to January 2015. Of which, 9,238 patients were identified with a diagnosis of AF. After excluding ineligible patients, a 1:1 propensity score matched cohort of 1,324 warfarin users and non-users were assembled. Results: VKA use was associated with both increased 90-day survival (hazard ratio, HR 0.47, p < 0.01) and 6-year survival (HR 0.76, p < 0.01); however, a trend indicated a stronger early benefit (p for time-interaction <0.01). Moderation analysis showed that patients' age and clinical history of stroke strongly influenced warfarin-related benefits on survival. Conclusion: VKA may provide an early survival benefit; however, this is partially offset later during the follow-up. In addition, heterogeneous risk-benefit profiles were observed among subgroups of dialysis-dependent patients with AF, further emphasizing the complexities of tailoring stroke prevention strategies in this population.

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The impact of warfarin on the rate of progression of aortic stiffness in hemodialysis patients: a longitudinal study

Cited by 38 publications

References 38 publications

Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population‐Based Gutenberg Health Study

Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population‐Based Gutenberg Health Study

Inactive Matrix Gla-Protein Is Associated With Arterial Stiffness in an Adult Population–Based Study

Patients' Characteristics Affect the Survival Benefit of Warfarin Treatment for Hemodialysis Patients with Atrial Fibrillation. A Historical Cohort Study

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